Alternative TEL-JAK2 fusions associated with T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia dissected in zebrafish

Background Chromosomal translocations resulting in alternative fusions of the human TEL (ETV6) and JAK2 genes have been observed in cases of acute lymphoblastic leukemia and chronic myelogenous leukemia, but a full understanding of their role in disease etiology has remained elusive. In this study potential differences between these alternative TEL-JAK2 fusions, including their lineage specificity, were investigated.

Design and Methods TEL-JAK2 fusion types derived from both T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia were generated using the corresponding zebrafish tel and jak2a genes and placed under the control of either the white blood cell-specific spi1 promoter or the ubiquitously-expressed cytomegalovirus promoter. These constructs were injected into zebrafish embryos and their effects on hematopoiesis examined using a range of molecular approaches. In addition, the functional properties of the alternative fusions were investigated in vitro.

Results Injection of the T-cell acute lymphoblastic leukemia-derived tel-jak2a significantly perturbed lymphopoiesis with a lesser effect on myelopoiesis in zebrafish embryos. In contrast, injection of the atypical chronic myelogenous leukemia-derived tel-jak2a resulted in significant perturbation of the myeloid compartment. These phenotypes were observed regardless of whether expressed in a white blood cell-specific or ubiquitous manner, with no overt cellular proliferation outside of the hematopoietic cells. Functional studies revealed subtle differences between the alternative forms, with the acute lymphoblastic leukemia variant showing higher activity, but reduced downstream signal transducer and activator of transcription activation and decreased sensitivity to JAK2 inhibition. JAK2 activity was required to mediate the effects of both variants on zebrafish hematopoiesis.

Conclusions This study indicates that the molecular structure of alternative TEL-JAK2 fusions likely contributes to the etiology of disease. The data further suggest that this class of oncogene exerts its effects in a cell lineage-specific manner, which may be due to differences in downstream signaling.

Electroretinography in streptozotocin diabetic rats following acute intraocular pressure elevation

Background
We consider whether pre-existing streptozotocin induced hyperglycemia in rats affects the ability of the eye to cope with a single episode of acute intraocular pressure (IOP) elevation.
Methods
Electroretinogram (ERG) responses were measured (−6.08 to 1.92 log cd.s.m−2) in anaesthetized (60:5 mg/kg ketamine:xylazine) dark-adapted (>12 h) adult Sprague–Dawley rats 1 week after a single acute IOP elevation to 70 mmHg for 60 min. This was undertaken in rats treated 11 weeks earlier with streptozotocin (STZ, n = 12, 50 mg/kg at 6 weeks of age) or citrate buffer (n = 12). ERG responses were analyzed to derive an index of photoreceptor (a-wave), ON-bipolar (b-wave), amacrine (oscillatory potentials) and inner retinal (positive scotopic threshold response, pSTR) function.
Results
One week following acute IOP elevation there was a significant reduction of the ganglion cell pSTR (−35 ± 11 %, P = 0.0161) in STZ-injected animals. In contrast the pSTR in citrate-injected animals was not significant changed (+16 ± 14 %). The negative component of the STR was unaffected by IOP elevation in either citrate or STZ-treated groups. Photoreceptoral (a-wave, citrate-control +4 ± 3 %, STZ +4 ± 5 %) and ON-bipolar cell (b-wave, control +4 ± 3 %, STZ +4 ± 5 %) mediated responses were not significantly affected by IOP elevation in either citrate- or STZ-injected rats. Finally, oscillatory potentials (citrate-control +8 ± 23 %, STZ +1 ± 17 %) were not reduced 1 week after IOP challenge.
Conclusions
The ganglion cell dominated pSTR was reduced following a single episode of IOP elevation in STZ diabetic, but not control rats. These data indicate that hyperglycemia renders the inner retina more susceptible to IOP elevation.

Insulin sensitivity not modulated 24 to 78 h after acute resistance exercise in type 2 diabetes patients

Background
The aim of this study was to describe the clinical characteristics, causative pathogens, clinical management and outcomes of patients presenting to a tertiary adult Australian intensive care unit (ICU) with a diagnosis of necrotizing fasciitis (NF).
Methods
This retrospective observational study was conducted in a 19-bed, level III, adult ICU in a 450-bed tertiary, regional hospital. Clinical databases were accessed for patients diagnosed with NF and admitted to The Geelong Hospital ICU between 1 February 2000 and 1 June 2011. Information on severity of sepsis, surgical procedures and microbiological results were collected.
Results
Twenty patients with NF were identified. The median age was 52.5 years and 38% were female. The overall mortality rate was 8.3%. Common co-morbidities were diabetes (21%) and heart failure (17%), although 50% of patients had no co-morbidities. Group A Streptococcus was the identified pathogen in 11 (46%) patients, and Streptococcus milleri group in 5 (21%) patients. Hyperbaric oxygen therapy was not used in the majority of patients. The initial antibiotics administered were active against subsequently cultured bacteria in 83% of patients. Median time to surgical debridement was 20 h. Diagnosis and management was delayed in the nosocomial group.
Conclusions
This study reports physiological data, aetiology and therapeutic interventions in NF for an adult tertiary hospital. We demonstrate one of the lowest reported mortality rates, with early surgical debridement being achieved in the majority of patients. The main delay was found to be in the diagnosis of NF.

An ICT enabled conceptual framework for determining epidemic susceptibility and acute type response : an exemplar from India

In a developing nation such as India, the national government is pursuing the pathway of ICT supported decentralized programs, to combat endemics, in the social contexts of each State. The State of Kerala, which has been an exemplar for development, has become susceptible to endemics, brought in by urbanization and non-resident Indian population and compounded by environmental disasters. In this paper, the authors contend that the psyche of the community which has changed from social amity to self-interest need to be re-awakened with the power of ICTs and Internet, so as to efficiently combat endemics. The authors also propose a preliminary framework for emergency responses based on existing ICT systems, recommended by the national government, to fit the context.

A distinct DNA methylation signature defines pediatric pre-B cell acute lymphoblastic leukemia

Pre-B cell acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy and remains one of the highest causes of childhood mortality. Despite this, the mechanisms leading to disease remain poorly understood. We asked if recurrent aberrant DNA methylation plays a role in childhood ALL and have defined a genome-scale DNA methylation profile associated with the ETV6-RUNX1 subtype of pediatric ALL. Archival bone marrow smears from 19 children collected at diagnosis and remission were used to derive a disease specific DNA methylation profile. The gene signature was confirmed in an independent cohort of 86 patients. A further 163 patients were analyzed for DNA methylation of a three gene signature. We found that the DNA methylation signature at diagnosis was unique from remission. Fifteen loci were sufficient to discriminate leukemia from disease-free samples and purified CD34+ cells. DNA methylation of these loci was recurrent irrespective of cytogenetic subtype of pre-B cell ALL. We show that recurrent aberrant genomic methylation is a common feature of pre-B ALL, suggesting a shared pathway for disease development. By revealing new DNA methylation markers associated with disease, this study has identified putative targets for development of novel epigenetic-based therapies.

The acute effects of caffeine in a sugar-sweetened beverage on energy consumption

Background: It has been suggested that those who are habitually high caffeine consumers ingest greater quantities of snack foods both in and outside the laboratory. Sugar-sweetened beverages (SSBs) are a major contributor to caffeine consumption and evidence links SSB consumption with poor dietary intake.

Objective: To determine whether varying the concentration of caffeine in SSBs influences snack food consumption and energy intake.

Methods: Caffeine taste thresholds were assessed using the International Standards Organization method for assessing taste sensitivity. In a crossover study design, participants (n=23, 26±5 years old, 58% female) were provided with a standardized meal on 4 days and simultaneously consumed SSBs with varied levels of caffeine (0, 0.67, 1.16, and 1.65 mM). The intake of food and beverage was recorded following each meal session.

Results: A one way between groups analysis of variance revealed no significant main effect of caffeine concentration on consumption of SSBs [F (3, 92)=0.154, p=0.927] or food [F (3, 92)=0.305, p=0.822]. Pearson correlation analysis identified no significant correlations between the amount of food and SSB consumed (R=−0.031–0.415, p=0.062–0.893), or the amount of food and SSB consumed with body mass index and waist circumference (R=0.000 to −0.380, p=0.073–0.999). An individual's oral sensitivity to caffeine was not associated with SSB consumption (R=0.045 to −0.309, p=0.152–0.839) or the consumption of food (R=−0.052 to −0.327, p=0.128–0.812).

Conclusions: The concentration of caffeine in SSBs did not influence the amount of food or SSB consumed.

Risk factors for incident delirium in acute medical in-patients. A systematic review

Review question/objective
What risk factors are associated with incident delirium in adult patients during an acute medical hospitalisation?
More specifically, the objectives are to:
Identify and synthesise the best available evidence on the factors which are associated with delirium in adult patients admitted to acute medical facilities.

Types of participants
This review will consider studies that include adults (defined as 18 years and above) who were admitted to an acute medical setting (e.g. general medical units, stroke units, short stay units and neuromedical units) who were not delirious on admission (in order to differentiate incident delirium) but who developed incident delirium during hospitalisation

The review will exclude patients who were:
- critically ill and admitted to specialist unit e.g. ICU or CCU
- admitted for any type of surgery
- admitted for alcohol related reasons
- admitted to psychiatric facility
These patients will be excluded in order to determine factors that may be exclusive to the medical in patient setting.

Types of intervention(s)/phenomena of interest
This review will consider studies that evaluate any risk factors that may contribute to the development of delirium during in-patient hospitalisation. The review will look at factors present on admission (predisposing) and also factors that may occur during hospitalisation (precipitating) that contribute to incident delirium.

Types of outcomes
This review will consider studies that include the following outcome measures: the incidence of delirium as related to individual risk factors.

Characteristics and outcomes of patients requiring unplanned transfer from subacute to acute care

The study aims to identify the reasons for, and outcomes from, unplanned transfers from subacute care to acute care. A retrospective patient record review of patients requiring unplanned transfer from subacute to an acute care emergency department (ED) from 1 July 2008 to 30 June 2009 was undertaken. Data collected included patient demographics, clinical characteristics in preceding transfer, and on ED arrival and outcome data. There were 136 patients included in the study with a median age of 81 years. The most common reasons for transfer were respiratory problems and altered conscious state. In the 24 h preceding transfer, 92.6% of patients had ≥ 1 physiological abnormality and 10.3% of patients had no physiological parameters documented. On ED arrival, 75% of patients had physiological abnormalities. Hospital admission occurred in 75% of patients and the inpatient mortality rate was 14.7%. Factors associated with inpatient mortality were tachypnoea and severe hypoxaemia in 24 h preceding transfer and tachypnoea, hypoxaemia, hypoxaemia, severe hypoxaemia and hypothermia on ED arrival. Patients requiring unplanned transfer had higher inpatient mortality than older hospital users. Reasons for unplanned transfer reflect known predictors of in-hospital adverse events so predictive use of physiological data and patient characteristics might optimize patient safety.